Red Upconverter Nanocrystals Functionalized with Verteporfin for Photodynamic Therapy Triggered by Upconversion.
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ABSTRACT:
SUBMITTER: Miletto I
PROVIDER: S-EPMC9266923 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Water-soluble upconversion nanoparticles (UCNPs) that exhibit significant ultraviolet, blue, and red emissions under 980-nm laser excitation were successfully synthesized for performing near infrared (NIR)-triggered photodynamic therapy (PDT). The lanthanide-doped UCNPs bearing oleate ligands were first exchanged by citrates to generate polyanionic surfaces and then sequentially encapsulated with NH?-terminated poly(amido amine) (PAMAM) dendrimers (G4) and chlorine6 (Ce6) using a layer-by-layer (LBL) absorption strategy. Transmission electron microscopy and X-ray diffraction analysis confirm that the hybrid UCNPs possess a polygonal morphology with an average dimension of 16.0 ± 2.1 nm and ?-phase crystallinity. A simple calculation derived through thermogravimetric analysis revealed that one polycationic G4 dendrimer could be firmly accommodated by approximately 150 polyanionic citrates through multivalent interactions. Moreover, zeta potential measurements indicated that the LBL fabrication results in the hybrid nanoparticles with positively charged surfaces originated from these dendrimers, which assist the cellular uptake in biological specimens. The cytotoxic singlet oxygen based on the photosensitization of the adsorbed Ce6 through the upconversion emissions can be readily accumulated by increasing the irradiation time of the incident lasers. Compared with that of 660-nm lasers, NIR-laser excitation exhibits optimized in vitro PDT effects toward human breast cancer MCF-7 cells cultured in the tumorspheres, and less than 40% of cells survived under a low Ce6 dosage of 2.5 × 10-7 M. Fluorescence microscopy analysis indicated that the NIR-driven PDT causes more effective destruction of the cells located inside spheres that exhibit significant cancer stem cell or progenitor cell properties. Moreover, an in vivo assessment based on immunohistochemical analysis for a 4T1 tumor-bearing mouse model confirmed the effective inhibition of cancer cell proliferation through cellular DNA damage by the expression of Ki67 and ?H2AXser139 protein markers. Thus, the hybrid UCNPs are a promising NIR-triggered PDT module for cancer treatment.
| S-EPMC5618380 | biostudies-literature
Project description:Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting. In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work. Methods: The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers. The hybrid nanoparticles (ANG-IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer. Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry. The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay. Tumor accumulation of NPs was determined by a non-invasive in vivo imaging system (IVIS). The in vivo anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis. Results: In vitro data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR-triggered PDT and PTT. In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer in vitro, the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS. The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days). Conclusion: In vitro and in vivo data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival. The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM.
| S-EPMC5835948 | biostudies-literature
Project description:Elucidation of upconversion nanoparticles (UCNPs) that can be excited by near-infrared (NIR) light is an interesting topic in the field of photodynamic therapy (PDT). However, the PDT efficiency of conventional UCNPs is limited due to the low quantum yield and overheating effect of the 980 nm light source. In this study, a light source with a wavelength of 808 nm was used as an excitation source for Nd-doped UCNPs to solve the overheating effect. UCNPs with a core@shell structure (NaYF4:Yb,Er,Nd@NaYF4:Yb,Nd) were synthesized to increase the upconversion emission efficiency. Dual-color emitting Er-doped UCNPs and dual photosensitizers (Chlorin e6 and Rose Bengal) were used for enhanced PDT. Each photosensitizer could absorb red and green emissions of the UCNPs to generate reactive oxygen species (ROS), respectively. The ROS generation in a dual photosensitizer system is significantly higher than that in a single photosensitizer system. Additionally, PDT induces immunogenic apoptosis. In this study, by utilizing a highly efficient PDT agent, PDT-induced apoptosis was studied by biomarker analysis.
| S-EPMC7179334 | biostudies-literature
Project description:Core-shell nanoparticles (CSNPs) with diverse chemical compositions have been attracting greater attention in recent years. However, it has been a challenge to develop CSNPs with different crystal structures due to the lattice mismatch of the nanocrystals. Here we report a rational design of core-shell heterostructure consisting of NaYF4:Yb,Tm upconversion nanoparticle (UCN) as the core and ZnO semiconductor as the shell for potential application in photodynamic therapy (PDT). The core-shell architecture (confirmed by TEM and STEM) enables for improving the loading efficiency of photosensitizer (ZnO) as the semiconductor is directly coated on the UCN core. Importantly, UCN acts as a transducer to sensitize ZnO and trigger the generation of cytotoxic reactive oxygen species (ROS) to induce cancer cell death. We also present a firefly luciferase (FLuc) reporter gene based molecular biosensor (ARE-FLuc) to measure the antioxidant signaling response activated in cells during the release of ROS in response to the exposure of CSNPs under 980?nm NIR light. The breast cancer cells (MDA-MB-231 and 4T1) exposed to CSNPs showed significant release of ROS as measured by aminophenyl fluorescein (APF) and ARE-FLuc luciferase assays, and ~45% cancer cell death as measured by MTT assay, when illuminated with 980?nm NIR light.
| S-EPMC4317689 | biostudies-literature
Project description:BackgroundPatients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) produces localised tissue necrosis but previous studies using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This study assessed a shorter acting photosensitiser, verteporfin.MethodsFifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg(-1) verteporfin. After 60-90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently.ResultsIn all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm(3) at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple's pancreaticoduodenectomy.ConclusionsVerteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.
| S-EPMC3974098 | biostudies-literature
Project description:Despite considerable effort to improve upconversion (UC) in lanthanide-doped nanocrystals (NCs), the maximum reported efficiencies remain below 10%. Recently, we reported on low Er3+- and Yb3+-doped NaYF4 NCs giving insight into fundamental processes involved in quenching for isolated ions. In practice, high dopant concentrations are required and there is a trend toward bright UC in highly doped NCs. Here, additional quenching processes due to energy transfer and migration add to a reduction in UC efficiency. However, a fundamental understanding on how concentration quenching affects the quantum efficiency is lacking. Here, we report a systematic investigation on concentration-dependent decay dynamics for Er3+ or Yb3+ doped at various concentrations (1-100%) in core and core-shell NaYF4 NCs. The qualitative and quantitative analyses of luminescence decay curves and emission spectra show strong concentration quenching for the green-emitting Er3+ 4S3/2 and NIR-emitting 4I11/2 levels, whereas concentration quenching for the red-emitting 4F9/2 level and the IR-emitting 4I13/2 level is limited. The NIR emission of Yb3+ remains efficient even at concentration as high as 60% Yb3+, especially in core-shell NCs. Finally, the role of solvent quenching was investigated and reveals a much stronger quenching in aqueous media that can be explained by the high-energy O-H vibrations. The present study uncovers a more complete picture of quenching processes in highly doped UC NCs and serves to identify methods to further optimize the efficiency by careful tuning of lanthanide concentrations and core-shell design.
| S-EPMC6369665 | biostudies-literature
Project description:Advanced ovarian cancer is the most lethal gynecological cancer, with a high rate of chemoresistance and relapse. Photodynamic therapy offers new prospects for ovarian cancer treatment, but current photosensitizers lack tumor specificity, resulting in low efficacy and significant side-effects. In the present work, the clinically approved photosensitizer verteporfin was encapsulated within nanostructured lipid carriers (NLC) for targeted photodynamic therapy of ovarian cancer. Cellular uptake and phototoxicity of free verteporfin and NLC-verteporfin were studied in vitro in human ovarian cancer cell lines cultured in 2D and 3D-spheroids, and biodistribution and photodynamic therapy were evaluated in vivo in mice. Both molecules were internalized in ovarian cancer cells and strongly inhibited tumor cells viability when exposed to laser light only. In vivo biodistribution and pharmacokinetic studies evidenced a long circulation time of NLC associated with efficient tumor uptake. Administration of 2 mg.kg-1 free verteporfin induced severe phototoxic adverse effects leading to the death of 5 out of 8 mice. In contrast, laser light exposure of tumors after intravenous administration of NLC-verteporfin (8 mg.kg-1) significantly inhibited tumor growth without visible toxicity. NLC-verteporfin thus led to efficient verteporfin vectorization to the tumor site and protection from side-effects, providing promising therapeutic prospects for photodynamic therapy of cancer.
| S-EPMC6896159 | biostudies-literature
Project description:A drug model photosensitizer-conjugated upconversion nanoparticles nanocomplex was explored for application in near-infrared photodynamic therapy. As near-infrared penetrates deeper into the tissue, the model is useful for the application of photodynamic therapy in deeper tissue. The nanocomplex that was synthesized had low polydispersity, and the upconversion nanoparticle was covalently conjugated with the photosensitizer. The robust bond could prevent the undesired premature release of photosensitizer and also enhance the singlet-oxygen generation. Singlet-oxygen generation rate from this nanocomplex was evaluated in solution. The photodynamic therapy effect was assessed with MCF-7 cells in two different methods, 3-(4,5-dimethylth-iazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and live/dead assay. The assay results showed that promising efficacy (>90%) can be achieved with a low concentration (50 ?g mL(-1)) of this nanocomplex and mild dosage (7 mW cm(-2)) of near-infrared laser treatment.
| S-EPMC4294652 | biostudies-literature
Project description:The aim of the present study was to monitor photodynamic angioocclusion with verteporfin in capillaries. Details of this process were recorded under a microscope in real-time using a high-sensitivity video camera. A procedure was developed based on intravenous (i.v.) injection of a light-activated drug, Visudyne, into the chorioallantoic membrane (CAM) of a 12-day-old chicken embryo. The effect of light activation was probed after 24 h by i.v. injection of a fluorescent dye (FITC dextran), and analysis of its fluorescence distribution. The angioocclusive effect was graded based on the size of the occluded vessels, and these results were compared with clinical observations. The time-resolved thrombus formation taking place in a fraction of the field of view was video recorded using a Peltier-cooled CCD camera. This vessel occlusion in the CAM model was reproducible and, in many ways, similar to that observed in the clinical use of verteporfin. The real-time video recording permitted the monitoring of platelet aggregation and revealed size-selective vascular closure as well as some degree of vasoconstriction. Platelets accumulated at intravascular junctions within seconds after verteporfin light activation, and capillaries were found to be closed 15 min later at the applied conditions. Larger-diameter vessels remained patent. Repetition of these data with a much more sensitive camera revealed occlusion of the treated area after 5 min with doses of verteporfin and light similar to those used clinically. Consequently, newly developed light-activated drugs can now be studied under clinically relevant conditions.
| S-EPMC2494573 | biostudies-other
Project description:Pancreatic cancer is notoriously difficult to treat and resistant to virtually all therapeutics including gemcitabine, the standard front line agent for palliative chemotherapy. Early clinical studies point to a potential role for photodynamic therapy (PDT) in the management of this deadly disease. Here we examine PDT with verteporfin for treatment of cells that are nonresponsive to gemcitabine and identify intracellular and extracellular factors that govern sensitivity to each modality.Using MTS we assess cytotoxicity of verteporfin-PDT in gemcitabine-treated nonresponsive populations from a panel of five pancreatic cancer cell lines representing a range of tumor histopathology and origin. We conduct Western blots for pro-/anti-apoptotic proteins bax and Bcl-XL to identify factors relevant to PDT and gemcitabine sensitivity. To examine the role of extracellular matrix influences we compare response to each modality in traditional cell culture conditions and cells grown on a laminin-rich basement membrane.All cell lines have gemcitabine nonresponsive populations (17-33%) at doses up to 1?mM while moderate total verteporfin PDT doses (1-6?µM?J/cm2) produce nearly complete killing. Our data shows that cells that are nonresponsive to sustained gemcitabine incubation are sensitive to verteporfin PDT indicating that the latter is agnostic to gemcitabine sensitivity. Verteporfin-based PDT decreases Bcl-XL and increases the bax/Bcl-XL ratio toward a pro-apoptotic balance. Insensitivity to gemcitabine is increased in cells that are adherent to basement membrane relative to traditional tissue culture conditions.Collectively these results indicate the ability of verteporfin-based PDT to bypass intracellular and extracellular cues leading to gemcitabine resistance and point to the emerging role of this therapy for treatment of pancreatic cancer.
| S-EPMC3211106 | biostudies-literature